Congestive heart failure is a common disorder with a high annual mortality rate of 20-45%. Nearly half these deaths are sudden, and many are likely the result of ventricular tachyarrhythmias. Most efforts to identify patients at highest risk for sudden death and to intervene to lower this risk have been remarkable unsuccessful, in large part due to a lack of understanding of the underlying mechanisms of arrhythmia. Investigation of these mechanisms is ideally conducted in a controlled model that affords analysis at whole organ, cellular, and molecular levels, and that minimizes the variable etiologies and therapeutic histories that typically complicate human studies. The canine pacing- tachycardia failure model appears highly suitable for this purpose as it displays a high incidence of malignant ventricular arrhythmias, and has many mechanical, biochemical, and molecular changes similar to those of human heart failure. This proposal tests the following hypothesis: 1) that this animal model indeed provides a relevant substrate to study arrhythmias of heart failure, 2) that these arrhythmias are associated with prolonged and increased spatial/temporal dispersion of repolarization (Q-T interval, action potential duration), and reduced threshold to triggered arrhythmias, 3) that two repolarizing potassium currents - the inward rectifier and outward transient current - are markedly reduced with development of heart failure in this model, contributing to repolarization delay and arrhythmia, and 4) that these changes are paralleled by reduced gene expression of the corresponding channel proteins, measureable by mRNA analysis of endomyocardial biopsies. Adult mongrel dogs are chronically instrumented for determination of chamber pressure-dimension mechanics in the conscious state. Dogs are ventricularly paced at 240 min-1 for 2-3 weeks, followed by 210 min-1 until development of heart failure. Holter monitors are obtained during weekly 24 hour pacing-off periods to study arrhythmia frequency, Q-T prolongation and variability. At baseline, 1-week, and heart failure time points, dogs are sedated, and endomyocardial biopsies obtained under sterile technique. Biopsies are processed by quantitative polymerase chain reaction to measure mRNA levels for the two above mentioned K+ channels, and for other 'marker' genes of heart failure such as SR-Ca2+-ATPase and phospholamban. Monophasic action potentials and cesium chloride provocation studies performed at these same times will measure repolarization abnormalities and test the hypothesis that the failure substrate bears mechanical similarities to long Q-T syndromes. Finally, at each of the three time points, a subset of animals will be sacrificed, and myocardial cells isolated for patch-clamp and single- channel recordings of repolarizing K+ currents. These studies aim at unifying recent data suggesting an important role of altered repolarization and in particular reduced outward K+ currents in arrhythmogenicity in congestive heart failure. Reduced gene expression of these channel proteins could prove to be a valuable marker for enhanced sudden death risk, as well as suggest future avenues for better targeted therapies.